Studies supported by this Program Project have shown that viral infections pose a threat to tolerized recipients of allogeneic transplants by breaking tolerance and inducing the rejection of the allografts. We also have previously demonstrated that viral infections generate virus-specific T cells that cross-react with allogeneic MHC antigens. Here we examine the discrete specificity behind virus-induced allospecific T cells and examine their significance in virus-induced allograft rejection. Specifically, we propose to examine the relationship between viral peptide specificity and allospecificity and how tolerization to alloantigens alters the virus-induced CTL response. We next will determine how viral infections impact the frequency of allospecific T cells in the memory pool and whether these memory allospecific T cells render a host more difficult to tolerize by peripheral and central (bone marrow chimeric) models of anti-CD154-induced tolerization. Finally, we will determine whether the observed abrogation of tolerance and induction of allograft rejection by acute viral infections is a direct consequence of cross-reactivity in T cell responses between viral and allo-antigens. This work will be heavily interactive with studies proposed in Projects one and two and will utilize services from the Virology and Morphology Cores.